Glaucoma is a disease complex characterized chiefly by an increase in intraocular pressure that, if sufficiently high and persistent, leads to damage to the optic nerve. This can cause irreversible blindness. Glaucoma is classed in three groups: primary, secondary and congenital.
Primary glaucoma is subdivided into angle closure and open angle types, based on the configuration of the angle of the anterior chamber of the eye where reabsorption of the aqueous humor occurs. [See generally Becker and Shaffer "Diagnosis and Therapy of the Glaucomas," C. V. Moslry Co., St. Louis (1976); A. G. Gilman et al. (eds.), The Pharmacological Basis of Therapeutics, Chapter 6, pp. 113-14, MacMillan Publishing Co., lnc., New York (6th ed. 1980).]
Angle closure glaucoma is nearly always a medical emergency in which drugs are essential in controlling the acute attack, but the long-range management is usually based predominantly on surgery (e.g., peripheral or complete iridectomy). Primary open angle glaucoma (POAG), on the other hand, has a gradual, insidious onset and usually responds to drug therapy. Certain cases, however, may require laser or surgical intervention in addition to drug treatment; failure of medical treatment necessitates surgery.
In POAG there is no visible obstruction or abnormality in the trabecular meshwork. Nevertheless, it is widely postulated that most of the resistance to the outflow of aqueous humor occurs here in the meshwork. In this circumstance, contraction of the ciliary muscle enhances tone and alignment of the trabecular network to improve resorption and outflow of aqueous humor through the network to the canal of Schlemm.
A large number of drugs have been used in the treatment of glaucoma. Andrenergic blocking agents, for example, are of great value in the management of the primary as well as of certain categories of the secondary type (e.g., aphakic glaucoma, following cataract extraction); the congenital type rarely responds to therapy other than surgical treatment. Each of these drugs, however, suffers from undesirable side effects or a need for frequent reapplication or instillation by sustained release. In contrast, the method of the present invention provides for a sustained and profound effect from occasional dosing. The method of the present invention is useful for treating the pressure elevation in all types of glaucoma.
Acute angle closure glaucoma may be precipitated by the injudicious use of a mydriatic agent in patients over 40, or by a variety of factors that can cause pupillary dilatation or engorgement of intraocular vessels [Gilman et al., supra, p. 113]. The cardinal signs and symptoms often include marked ocular inflammation, a semidilated pupil, severe pain and nausea. Every effort must be made to reduce the intraocular pressure to the normal level and maintain it there for the duration of the attack. In general, the most important drug for treatment is an osmotic agent such as oral glycerol to induce intraocular dehydration. Treatment adjuncts include beta blockers such as timolol and carbonic anhydrase inhibitors. Some physicians prefer a choinergic such as pilocarpine in early treatment. Laser iridotomy has recently been found to have an important role in the management of angle closure glaucoma. The long-acting organophosphorus compounds are not indicated in angle closure glaucoma because of vascular engorgement and an increase in the angle block.
POAG and secondary glaucoma require careful consideration of the needs of the individual patient in selecting the drug or combination of drugs to be employed. The choices available include (1) parasympathomimetic agents (e.g., pilocarpine nitrate, 0.5 to 4%); (2) anti-ChE agents that are short acting (e.g., physostigmine salicylate, 0.02 to 1%) and long acting (demecarium bromide, 0.125 to 0.25%; echothiophate, 0.03 to 0.25%; isoflurophate, 0.005 to 0.2%); and, paradoxically, (3) sympathomimetic agents (e.g., epinephrine, 1 to 2%; dipivalyl epinephrine (0.1%). Drugs of the last-mentioned class are often most effective when used in combinations with AChE inhibitors or cholinergic agonists. They reduce intraocular pressure by decreasing secretion of aqueous humor, and they prevent engorgement of small blood vessels. Timolol, an adrenergic antagonist, has also been found to be effective in reducing intraocular pressure. Timolol does not cause pupillary constriction but appears to act by reducing the production of aqueous humor. Timolol is long acting, and administration is at 12-hour intervals. Timolol has become very popular in the treatment of POAG because of its effectiveness and lack of side effects. Despite the convenience of less frequent administration and the high potency of long-acting anti-cholinesterase agents, their use entails a greater risk of development of lenticular opacities and untoward autonomic effects which limit their usefulness.
Methacholine, carbacol, pilocarpine and aceclidine are muscarinic agents which can be used to reduce intraocular pressure [Gilman et al., supra, Chapter 5, pp. 96-98]. Methacholine, in concentrations up to 20%, in combination with neostigmine bromide, 5%, instilled intraconjunctivally at frequent intervals, has been recommended for the emergency treatment of acute attacks of narrow-angle glaucoma. Carbachol has been used (0.25 to 3.0%) for chronic therapy of noncongestive, wide-angle glaucoma. Pilocarpine, when applied locally to the eye, causes pupillary constriction, spasm of accomodation, and a transitory rise in intraocular pressure, followed by a more persistent fall. Aceclidine (Glaucostat) is a synthetic compound which is approximately as effective as pilocarpine in reducing intraocular pressure in glaucoma.
Intraocular pressure may be effectively controlled without the stinging sensation an myopia experienced immediately after the application of pilocarpine solution by the use of a drug-delivery system called Ocusert which achieves a sustained release of pilocarpine (20 or 40 .mu.g per hour) for at least 7 days. However, many patients find the foreign body uncomfortable and have difficulty with the insertion of the device, which explains its current limited usefulness.
Anti-cholinesterase (AChE) agents produce a fall in intraocular pressure in both types of primary glaucoma, chiefly by lowering the resistance to outflow of the aqueous humor. Effects on the volumes of the various intraocular vascular beds (e.g., those of the iris, ciliary body, etc.) and on the rate of secretion of the aqueous humor into the posterior chamber may contribute secondarily to the lowering of pressure, or conversely may produce a rise in pressure preceding the fall. In narrow-angle glaucoma, the aqueous outflow is facilitated by the freeing of the entrance to the trabecular space at the canal of Schlemm from blockade by the iris, as the result of the drug-induced contraction of the sphincter muscle of the iris. Use of anti-cholinesterase agents has been limited by their side effects which include formation of iris cysts, headaches and cataracts.
Timolol is a nonselective .beta.-adrenergic antagonist [Gilman et al., supra, p. 195]. Timolol maleate (e.g., Timoptic, Merck, Sharpe & Dohme) is an ophthalmic preparation used for treatment of POAG aphakic glaucoma and secondary glaucoma. Timolo does not change the size of the pupil or the tone of the ciliary body, and it does not interfere with vision. The duration of beneficial effect is about 7 hours. The side effects are minimal, although systemic absorption of the drug can occur, leading to slowing of the heart, so the drug should be used with caution in individuals with asthma, heart block or heart failure.
Epinephrine (0.25 to 2%) or dipivalyl epinephrine (0.1%) are used to treat open angle glaucoma, reducing the intraocular pressure by their local vasoconstrictor actions, which decreases production of aqueous humor [Gilman et al., supra, p. 171].
It is thought that carbonic anhydrase may play a role in the formation of aqueous humor. The carbonic anhydrase inhibitor acetazolamide reduces the rate of aqueous humor formation, thereby lowering intraocular pressure in patients with glaucoma.
Ganglionic blocking agents can impair transmission in the ciliary ganglion, causing incomplete mydriasis and partial loss of accommodation.
The compound 12(R)-HETE was first identified as an arachidonic acid metabolite in skin lesions [M. Woolard "Stereochemical Difference between 12-Hydroxy-5,8,10,14-Eicosatetraenoic Acid in Platelets And Psoriatic Lesions," Biochem. Biophys. Res. Comm. 136, pp. 169-76 (1986)]. Recently Schwartzman, et al., have demonstrated that 12(R)-HETE is not a lipoxygenase derived metabolite but, rather, a cytochrome P.sub.450 -dependent metabolite of arachidonic acid produced, inter alia, in the bovine corneal epithelium. [Schwartzman et al., "12(R)-HETE - A Cytochrome P.sub.450 -Dependent Arachidonate Metabolite That Inhibits Na.sup.+ -K.sup.+ -ATPase in the Cornea," Proc. Natl. Acad. Sci. (USA), Vol. 84, pp. 8125-29 (1987)].
Cytochrome P.sub.450 has been observed in several eye tissues including cornea, ciliary body, retinal pigment, pigment epithelium, lens epithelium and retina [N. Abraham et al., "Presence of Heme Oxygenase And NADPH Cytochrome P.sub.450 (c) Reductase In Human Corneal Epithelium," Invest. Opthalmol. Vis. Sci., 28, pp. 1464-72 (1987)]. In bovine tissues, the ciliary body is known to have the highest level of drug metabolizing enzymes (presumably among eye tissues). Enzyme activity in the bovine corneal epithelium is about half of that found in ciliary bodies. [Id.]